Attenuation of pattern recognition receptor signaling is mediated by a MAP kinase kinase kinase

Pattern recognition receptors (PRRs) play a key role in plant and animal innate immunity. PRR binding of their cognate ligand triggers a signaling network and activates an immune response. Activation of PRR signaling must be controlled prior to ligand binding to prevent spurious signaling and immune activation. Flagellin perception in Arabidopsis through FLAGELLIN‐SENSITIVE 2 (FLS2) induces the activation of mitogen‐activated protein kinases (MAPKs) and immunity. However, the precise molecular mechanism that connects activated FLS2 to downstream MAPK cascades remains unknown. Here, we report the identification of a differentially phosphorylated MAP kinase kinase kinase that also interacts with FLS2. Using targeted proteomics and functional analysis, we show that MKKK7 negatively regulates flagellin‐triggered signaling and basal immunity and this requires phosphorylation of MKKK7 on specific serine residues. MKKK7 attenuates MPK6 activity and defense gene expression. Moreover, MKKK7 suppresses the reactive oxygen species burst downstream of FLS2, suggesting that MKKK7‐mediated attenuation of FLS2 signaling occurs through direct modulation of the FLS2 complex.     

The relationship between maternal and offspring birth weights after maternal prenatal famine exposure: the Dutch Famine Birth Cohort Study

We examined the impact of famine-induced changes in maternal birth weight (MBW) on the association between MBW and offspring birth weight (OBW). Women born before, during, and after the Dutch Famine of 1944-1945 were interviewed at ages 41 to 46 years. Women (n = 582) and their children (n = 1,111) were included in the analysis if both mother and child were singleton and the child was not delivered preterm. Mean birth weight (BW) of women with first-trimester exposure (n = 110) was 154 g higher (p = 0.008), and mean BW of women with third-trimester exposure (n = 138) was 251 g lower (p < 0.001) than mean BW of unexposed women (n = 302). First-born offspring of women with first-trimester exposure were 72 g heavier (95% confidence interval [CI], -57 to 201; p = 0.27), and offspring of women with third-trimester exposure were 43 g lighter (95% CI, -170 to 79; p = 0.47) than offspring of unexposed women. Among unexposed women, each 100 g increase in MBW was associated with 25 g (95% CI, 12 to 37) increase in OBW (adjusted for maternal age, smoking, weight, and height and offspring sex). This association was attenuated in famine-exposed women (first-trimester change in OBW = 20 g per 100 g MBW; 95% CI, -1 to 41; third-trimester change in OBW = 14 g per 100 g MBW; 95% CI, -9 to 37). When MBW and trimester of maternal famine exposure were considered in a joint model, there was no independent effect of trimester of maternal famine exposure on OBW. Associations were less consistent for later-born offspring. We conclude that maternal prenatal famine exposure does not affect the association between maternal and offspring BW. Trimester of exposure was not a determinant of OBW, other than through its effect on MBW. Nevertheless, acute famine may impact on second-generation BW distributions indirectly, through its effect on the distribution of MBW.     

Neuropsychopharmacology and Neurogenetic Aspects of Executive Functioning: Should Reward Gene Polymorphisms Constitute a Diagnostic Tool to Identify Individuals at Risk for Impaired Judgment?

Executive functions are processes that act in harmony to control behaviors necessary for maintaining focus and achieving outcomes. Executive dysfunction in neuropsychiatric disorders is attributed to structural or functional pathology of brain networks involving prefrontal cortex (PFC) and its connections with other brain regions. The PFC receives innervations from different neurons associated with a number of neurotransmitters, especially dopamine (DA). Here we review findings on the contribution of PFC DA to higher-order cognitive and emotional behaviors. We suggest that examination of multifactorial interactions of an individual's genetic history, along with environmental risk factors, can assist in the characterization of executive functioning for that individual. Based upon the results of genetic studies, we also propose genetic mapping as a probable diagnostic tool serving as a therapeutic adjunct for augmenting executive functioning capabilities. We conclude that preservation of the neurological underpinnings of executive functions requires the integrity of complex neural systems including the influence of specific genes and associated polymorphisms to provide adequate neurotransmission.     

Consensus statement understanding health and malnutrition through a systems approach: the ENOUGH program for early life

Nutrition research, like most biomedical disciplines, adopted and often uses experimental approaches based on Beadle and Tatum’s one gene—one polypeptide hypothesis, thereby reducing biological processes to single reactions or pathways. Systems thinking is needed to understand the complexity of health and disease processes requiring measurements of physiological processes, as well as environmental and social factors, which may alter the expression of genetic information. Analysis of physiological processes with omics technologies to assess systems’ responses has only become available over the past decade and remains costly. Studies of environmental and social conditions known to alter health are often not connected to biomedical research. While these facts are widely accepted, developing and conducting comprehensive research programs for health are often beyond financial and human resources of single research groups. We propose a new research program on essential nutrients for optimal underpinning of growth and health (ENOUGH) that will use systems approaches with more comprehensive measurements and biostatistical analysis of the many biological and environmental factors that influence undernutrition. Creating a knowledge base for nutrition and health is a necessary first step toward developing solutions targeted to different populations in diverse social and physical environments for the two billion undernourished people in developed and developing economies.     

Regulation of TRH release by the cultured neonate rat pancreas

The TRH secretory responsiveness of the pancreatic islet cell clusters from newborn rat in organ culture was studied. Basal TRH secretion was stable over a 9-day period. The response to various secretagogues was tested on day 4. TRH secretion was stimulated by high potassium-induced depolarization and also through both cAMP and protein kinase-C dependent pathways. Like insulin, TRH release was stimulated by glucose and arginine and inhibited by somatostatin. These data suggest the existence of a common mechanism for TRH and insulin secretion by the pancreatic β-cells.     

Acute undernutrition is not associated with excess of females at birth in humans: the Dutch hunger winter

It has been suggested that maternal undernutrition results in adjustment of the sex ratio at birth, favouring females. We tested this hypothesis using births during the Dutch Hunger Winter of 1944-1945, an acute severe famine of seven months' duration. There was no evidence of an excess of female births among deliveries of human infants exposed to famine in any period in gestation. Indeed, among deliveries to women maximally exposed to famine prior to conception, there was an excess (odds ratio = 1.31, 95% CI 1.09-1.58; p = 0.004) of male offspring. Our data do not provide any support for acute and severe maternal undernutrition as a trigger for an increase in female conceptions or in male foetal deaths in human populations.     

Elimination of Mange Mites <Emphasis Type="Italic">Sarcoptes scabiei</Emphasis> var. <Emphasis Type="Italic">suis</Emphasis>from Two Naturally Infested Danish Sow Herds Using a Single Injection Regime with Doramectin

Attempts to eliminate Sarcoptes scabiei var. suis were made in 2 naturally infested sow herds, by intramuscular (IM) injection of doramectin (Dectomax^®, Pfizer, New York, USA). A single injection strategy was used. In one of the herds, the environment was treated with an acaricide following dry cleaning of floors, walls and equipment. In the second herd, no environmental treatment was performed. Results were measured by skin lesion scoring, ear scrapings to show Sarcoptes scabiei var. suis, and calculating rubbing index throughout the observation period of 20 months following treatment. Skin lesion scores decreased and stayed low following treatment for the entire observation period. Live Sarcoptes scabiei var. suis mites were isolated prior to treatment from both herds, but not following treatment. Rubbing index decreased following treatment, but was occasionally at or above 0.4. The results of these studies indicate that elimination of Sarcoptes scabiei var. suis from 2 naturally infested herds was successful, using doramectin in a single injection strategy. Precautions must be taken to ensure adequate dosing of every pig, and to avoid reinfestation due to poor biosecurity.     

Energy restriction during childhood and early adulthood and ovarian cancer risk

Dietary energy restriction may protect against cancer. In parts of The Netherlands, mostly in larger cities, periods of chronically impaired nutrition and even severe famine (Hunger Winter 1944-1945) existed during the 1930s and World War II (1940-1945). We studied the association between energy restriction during childhood and early adulthood on the risk of ovarian cancer later in life. In 1986, the Netherlands Cohort Study was initiated. A self-administered questionnaire on dietary habits and other cancer risk factors was completed by 62,573 women aged 55-69 years at baseline. Follow-up for cancer was established by record linkage to the Netherlands Cancer Registry. After 16.3 years of follow-up, 364 invasive epithelial ovarian cancer cases and 2220 subcohort members (sampled from the total cohort directly after baseline) with complete information confounders were available for case-cohort analyses. In multivariable analysis, ovarian cancer risk was lower for participants with an unemployed father during the 1930s (Hazard Ratio (HR), 0.70; 95% Confidence Interval (CI), 0.47-1.06) compared to participants with an employed father as well as for participants living in a city during World War II (HR, 0.69; 95% CI, 0.54-0.90) compared to participants living in the country-side. Residence in a Western City during the famine (Hunger Winter) was not associated with a decreased risk. Our results show a relation between proxy variables for modest energy restriction over a longer period of time during childhood or early adulthood and a reduced ovarian cancer risk.     

Spatio-temporal distribution of sperm whales (Physeter macrocephalus) off Kaikoura,New Zealand,in relation to bathymetric features

Using a shore-based station we monitored the position of sperm whales (Physeter macrocephalus) within the Kaikoura submarine canyon from 2010 to 2012. We tracked sperm whales using a theodolite station for a total of 290 days. We extracted the distance from the nearest coast, the depth and the bathymetric slope using ArcGIS 10.1. We estimated the seasonal spatial distribution of sperm whales using general additive models. The distribution varied significantly between seasons; individuals were found in deeper water and further offshore in the spring than in winter. This study improved our understanding of the variability of sperm whale distribution patterns off Kaikoura. We determined that the distribution was linked to the bathymetric features and we hypothesized that whales adapted their use of the submarine canyon in relation to food aggregation. We would encourage further studies to evaluate the sperm whale relationship with oceanographic variables off Kaikoura.